1. Field of the Invention
The present invention relates to transdermal drug delivery systems. In particular, the present invention relates to transdermal drug delivery systems for delivering a therapeutically effective amount of a drug that includes a parent drug and a prodrug. The present invention, in particular, relates to transdermal drug delivery systems for delivering steroids, and to methods of making and using the same.
2. Description of the Related Art
The use of a transdermal drug delivery system, for example a pressure-sensitive adhesive containing a drug, as a means for administering therapeutically effective amounts of the medicament is well known. Such known delivery systems involve incorporation of a drug into a carrier such as a polymeric and/or a pressure-sensitive adhesive formulation or other forms of carriers. The pressure-sensitive adhesive must adhere effectively to the skin and permit migration of the drug from the carrier through the skin and into the bloodstream of the patient.
Steroids such as estradiol and norethindrone are especially well known for use in transdermal drug delivery systems, in particular, as hormone replacement therapy. These steroids may be administered singularly, such as the estradiol transdermal drug delivery system sold under the trademark Vivelle7 and Vivelle-Dotθ manufactured by Noven Pharmaceuticals, Inc. of Miami, Fla. See also U.S. Pat. No. 6,221,383. Alternatively, two or more steroids may be administered together, such as the estradiol/norethindrone acetate transdermal drug delivery system sold under the trademark CombiPatch® also manufactured by Noven Pharmaceuticals. See also U.S. Pat. No. 6,221,383. See also U.S. Pat. No. 5,474,783.
Transdermal drug delivery systems with more than one drug are generally more difficult to formulate in view of different interactions with each drug and the carrier, excipients, etc., even the other drug present. In addition, government agencies that regulate pharmaceutical products, such as the FDA in the United States, require more testing of multiple drugs, individually as well as together to establish efficacy. Thus, when a drug, such as a steroid is administered, it is generally administered in one form only (e.g., norethindrone or norethindrone acetate). See, e.g., U.S. Pat. No. 6,149,935.
The use of a steroid as an additive to act as a crystallization inhibitor in transdermal drug delivery devices where the drug is a hormone is described in WO 99/15156. WO 99/15156 teaches the steroid is present in the device in an amount insufficient to provide significant pharmaceutical or physiological effect. Other patents include U.S. Pat. Nos. 5,633,242; 4,906,169; 5,711,962; 6,153,216; 5,898,032; 5,811,117; and 6,024,974.
One problem in the delivery of drugs, such as steroids from transdermal drug delivery systems lies in the rate of drug release (commonly called “flux” or “permeation rate”) from the transdermal system. Specifically, there are many applications in which it would be desirable to have a greater flux of drug (e.g., steroid) from the system. There are also many applications in which it would be desirable to have a decreased flux of drug (e.g., steroid) from the system. In other words, one problem in transdermal drug delivery lies in controlling the transfer of drug from the composition, across the skin and into the subject's bloodstream, thus, controlling the blood profile level of the drug.
One known method for selectively controlling the permeation rate of a drug from a transdermal composition is described in U.S. Pat. No. 5,474,783, assigned to the assignee of the present invention. In this patent, two or more polymers are used in combination to adjust the solubility of the drug in the carrier system. While this method of controlling permeation rate generally works well, it is not always readily possible to control the permeation rate of the drug in the desired manner, such as to achieve a longer or shorter duration of drug delivery and to increase or delay onset of a therapeutic effect.
Another problem in the delivery of drugs, in particular steroids, is the tendency for drugs (e.g., steroids) to crystallize in the carrier of the transdermal system. This results in less steroid being available for transdermal administration. Although the addition of solubilizing agents, such as PVP, help to inhibit crystallization, there are some applications where it is desirable to have a greater crystal inhibiting effect.
U.S. Pat. No. 6,368,616 B1 discloses two phase (aqueous and oily) liquid compositions comprising at least: (A) an NSAID; (B) an alcohol (defined as melt point depressing agent, column 4, line 60); (C) water; and optionally (D) a second melt point depressing agent. The compositions are described as having two phases, with substantially melted solids at 25° C. The “second melt point depressing agents,” referred to in the '616 patent are defined as solvents, enhancers, adjuvants or drugs, such as anesthetics or NSAIDs.
U.S. Pat. No. 4,529,601 discloses combination of two different local anesthetic base drugs that melt together at room temperature. Preferred melting points are below 40° C., more preferably, below 25° C.